Milnacipran (the trade name is Ixel, and the chemical name is 1-phenyl-2-(aminomethyl)cyclopropane-N,N-diethyl carboxamide) is a antidepressant which is developed by FABRE MEDICAMENT SA PIERRE and is launched in 1997. It is reported that said drug is also used to treat fatigue, pain, fibromyalgia, Irritable bowel syndrome and the like. At present, it is mostly sold in the form of milnacipran hydrochloride. Milnacipran belongs to dual inhibitors of serotonin and norepinephrine reuptake (SNRI), which is the fourth generation antidepressant and can can inhibit both of serotonin and norepinephrine reuptake, with similar action strength. It is mainly useful to treat depression, especially major depression. There are 22 countries approved milnacipran for treating depression at present. Among of the antidepressants, milnacipran has the similar efficacy as TCAs and SSRIs, less drugs interaction, obviously less adverse reaction than TCAs, and less adverse reaction than SSRIs in some aspects, and when comparing with SSRIs, it has the similar efficacy, but more quickly in taking effect, the time of taking effect of which is about two weeks, due to milnacipran's ability of plasma protein-binding is lower and unsaturated, and without metabolism through the cytochrome P450 system, this means the medication is not likely to interact with other medications. Because milnacipran's half-life is relatively shorter, it have advantage of no residual effect after treatment, therefore it has fine tolerance and security.
The structural formula of milnacipran hydrochloride is as follows:

In 1992, a resolution had been approved by American Food and Drug Administration (FDA) and The European Committee for Proprietary Medicinal Products, which encouraged drugs with chiral center were in optically pure form for marketing authorization; in 1996, a project had been proposed by FDA that drugs with chiral center must be in optically pure form when it is applying for marketing authorization. There are two chiral center in the molecular structure of milnacipran, it should be two group of enantiomers-four compounds in theory. Due to the molecular configuration, the cis-isomer is the mainly synthetic product, that exist in two forms of optically enantiomers: the dextrogyral enantiomer of cis-milnacipran hydrochloride Z-(1 S,2R) and the levogyral enantiomer of cis-milnacipran hydrochloride Z-(1R,2S). The US patent US 2004/0162334, US 20060014837 and Chinese patent CN 1699332A have carried out detailly research on the single enantiomer of milnacipran, and the result indicates that the dextrogyral enantiomer of milnacipran hydrochloride had activity which was significantly higher than racemic milnacipran, with less risk of cardiovascular disturbances and tissue and organ organic toxicity.
The molecular structural formula of the two chiral enantiomers of milnacipran hydrochloride are as follows:

At present, the method for preparing optically pure milnacipran is mostly the asymmetric synthesis method, Bonnaud et al. resolved racemic γ-butyrolactone (1-phenyl-3-oxa-bicyclo[3.1.0]hexane-2-ketone) as starting material by R-(+)-phenyl ethylamine, the obtained optically active γ-butyrrolactone was separated by chiral stationary phase method, then by which as intermediate target product could be synthesized (Bonnaud et al., 1985, Journal of Chromatography, Vol. 318: 398-403); Shuto, S. et al. adopted optically epichlorohydrin and benzacetonitril as starting material, the optically fused γ-butyrrolactone was obtained by hydrolysis after nucleophilic substitution is performed twice in the presence of sodium amide. Then the ring of γ-butyrrolactone was opened to liberate hydroxyl group, substituted by azide group, reduced to give (+) and (−)-milnacipran (Shuto et al., Tetrahedron letters, 1996 Vol. 37: 641-644); Grard et al. separated racemic milnacipran to give optically pure milnacipran as well by high performance capillary electrophoresis chirality mehod. (Grard et al., 2000, Electrophoresis 21: 3028-3034); Doyle and Hu adopt phenylacetic acid as starting material, optically pure milnacipran can be obtained after asymmetric catalysis (Doyle and Hu, 2001, Advanced Synthesis and Catalysis, Vol. 343: 299-302). In a word, both of the asymmetric synthesis method and the chromatography method can give optically pure milnacipran with higher e.e.value (enantiomeric excess), but with complex operation and high cost.